This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We hypothesized that interaction between CD4+ T cells and professional antigen presenting cells is insufficient in HCV infected individuals, and that the resultant failure to generate and maintain a robust CD4+ T helper response contributes to viral persistence through alteration of the CD8+ T cell effector response. We have successfully characterized the phenotype of HCV specific T cells and have found that the cells express high levels of PD-1 and low levels of CD127, an exhausted phenotype correlating with poor effector function. Recently we showed that these cells co-express the costimulatory molecule CD86 during acute infection but rapidly lose this expression with the transition to viral persistence. This suggests that the balance between co-stimulatory and co-inhibitory molecules early in infection may influence infection outcome. We have also identified a complete panel of HCV epitopes to which HCV specific T cells should respond which will now allow for identification of specific immune deficits that may be targets for immune augmentation. Together, these studies will help unravel the interplay between the APC and the T cell and elucidate mechanistic failures in the antiviral response. Importantly, we recently submitted two manuscripts showing, in our murine model systems, that intrahepatic APC and, specifically, hepatic stellate cells are critical mediators of the intrahepatic immune response. HSC are the cell type responsible for fibrosis in chronic HCV infection;however, we have also recently shown that in the presence of TGFb, and in a retinoic acid-dependent manner, they contribute to the development of T regulatory cells.